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Nat Commun. 2018 Dec 18;9(1):5375. doi: 10.1038/s41467-018-07787-6.

SCL/TAL1 cooperates with Polycomb RYBP-PRC1 to suppress alternative lineages in blood-fated cells.

Author information

1
Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
2
Medimmune, Granta Park, CB21 6GH, Cambridge, UK.
3
Haematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
4
MRC Centre for Regenerative Medicine, SCRM Building, The University of Edinburgh, Edinburgh, EH16 4UU, UK.
5
Computational Biology Research Group, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
6
Wolfson Imaging Centre, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
7
FACS Facility, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
8
Genome Engineering Facility, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
9
Oxford National Institute for Health Research, Biomedical Research Centre, Haematology Theme, Oxford University Hospital, Oxford, OX3 9DU, UK.
10
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
11
Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK. catherine.porcher@imm.ox.ac.uk.

Abstract

During development, it is unclear if lineage-fated cells derive from multilineage-primed progenitors and whether active mechanisms operate to restrict cell fate. Here we investigate how mesoderm specifies into blood-fated cells. We document temporally restricted co-expression of blood (Scl/Tal1), cardiac (Mesp1) and paraxial (Tbx6) lineage-affiliated transcription factors in single cells, at the onset of blood specification, supporting the existence of common progenitors. At the same time-restricted stage, absence of SCL results in expansion of cardiac/paraxial cell populations and increased cardiac/paraxial gene expression, suggesting active suppression of alternative fates. Indeed, SCL normally activates expression of co-repressor ETO2 and Polycomb-PRC1 subunits (RYBP, PCGF5) and maintains levels of Polycomb-associated histone marks (H2AK119ub/H3K27me3). Genome-wide analyses reveal ETO2 and RYBP co-occupy most SCL target genes, including cardiac/paraxial loci. Reduction of Eto2 or Rybp expression mimics Scl-null cardiac phenotype. Therefore, SCL-mediated transcriptional repression prevents mis-specification of blood-fated cells, establishing active repression as central to fate determination processes.

PMID:
30560907
PMCID:
PMC6299140
DOI:
10.1038/s41467-018-07787-6
[Indexed for MEDLINE]
Free PMC Article

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